The goal of this project is to characterize the risk of Parkinson?s disease (PD) conferred by exposure to the solvents trichloroethylene (TCE) and tetrachloroethylene (PERC) in drinking water at Marine Base Camp Lejeune, North Carolina. Occupational exposure to the common industrial solvent trichloroethylene (TCE) was implicated in a cluster of PD in a small manufacturing plant in 2008. We replicated this observation in a study of discordant twins, in which we found a 6-fold risk associated with occupational exposure to TCE and 10-fold risk for PERC. Animal studies using orally-administered TCE strongly support the biological plausibility of these observations, and faithfully recapitulate the key pathologic characteristics of PD: mitochondrial impairment, intra-neuronal aggregation of phosphorylated alpha-synuclein protein, and regionally-specific degeneration of nigrostriatal dopaminergic neurons. Strikingly, despite the fact that TCE and PERC are present in 1/3 of US drinking water supplies and are detectable in most blood and breast milk, no human studies to date have assessed the risk of PD from TCE or PERC in drinking water. In the best documented large-scale contamination in US history, the drinking water supplied to up to 1 million residents of Marine Base Camp Lejeune in North Carolina was contaminated with TCE and PERC from 1953 until 1987. The Agency for Toxic Substances and Disease Registry (ATSDR) has developed detailed time- and address-specific exposure estimates for former residents throughout this time period. During 1975- 1985, the period of maximal contamination, the estimated median TCE level in drinking water was 366 ug/L, more than 70-fold the EPA maximum allowable level. Peak exposure levels were several hundred-fold higher. In 2017, after review by the Institute of Medicine, the VA issued guidelines designating PD as a presumptive service-connected illness for former Lejeune veterans. However, despite the fact that the VA has designated PD as service connected for former Lejeune residents, and the enormous financial consequences thereof, the risk from TCE and PERC in drinking water in humans has never been directly studied. What is needed to establish this relationship and to quantify and modify the risk for past, present and future exposed populations is an unbiased estimate of exposure and disease risk. In this project, we will link ATSDR objective site- and time-specific exposure estimates with comprehensive diagnostic and health care data available in Veterans Health Administration (VHA) electronic medical records (EMR) and associated databases to determine, for the first time, the risk of PD associated with oral exposure to TCE and PERC. The VHA EMR contains health and benefits data on more than 25,000,000 veterans, and includes detailed clinical, pharmacy, laboratory, demographic, service-related and other data going back decades. We will utilize the exceptional VHA EMR resources to 1) test the hypothesis that the risk of PD is greater in Marines who resided at Camp Lejeune (contamination present) than in Marines who resided at Camp Pendleton (contamination absent); 2) test the hypothesis that the risk of PD is associated with higher exposure to TCE or PERC in drinking water, or longer duration of residence at Camp Lejeune; and 3) test the hypothesis that higher exposure to TCE or PERC, or longer duration at Camp Lejeune is associated with a more severe PD phenotype (e.g., earlier onset of dementia, fractures, psychosis, motor fluctuations, death). High quality, objective environmental exposure metrics simply do not exist for late-life disorders such as PD. The unfortunate circumstances of the 35-year contamination of drinking water supplied to Marine Base Camp Lejeune Veterans offers a singular opportunity to definitively characterize the degree of risk from TCE and PERC, two of the most common contaminants in US drinking water. Identifying and characterizing the risk of PD will empower exposed Veterans and advance ongoing efforts to implement disease preventing therapeutic strategies in those Veterans at highest risk.